Function of linaclotide in irritable bowel syndrome

2018-10-09

Introduction

Linaclotide, sold under the brand name Linzess, is a synthetic tetradecapeptide and guanylate cyclase (GC-C) receptor agonist which is a class of compounds that increase the intra- and extracellular cyclic guanosine monophosphate (cGMP) concentrations by binding to the heat-stable enterotoxin receptors. Linaclotide is composed of fourteen amino acid residues in a linear sequence and three intrachain disulfide bonds. It is developed for the treatment of irritable bowel syndrome (IBS), especially for the patients with constipation and chronic idiopathic constipation (CIC). Notice that there is a warning to not use the drug in children less than six years old and to avoid in people aged between six and eighteen years old because of the risk of serious dehydration.

Pharmacologic action

Irritable bowel syndrome (IBS) is a functional disorder with a series of signs and symptoms, including abdominal pain, diarrhea, constipation, vomiting and changes in the pattern of gastrointestinal movements. As no treatments can cure it yet, drugs are used to improve symptoms. As an agonist of GC-C, linaclotide and its active metabolite activate GC-C and lead to intracellular and extracellular increase of cGMP, which will induce the secretion of chloride and bicarbonate into bowel lumen by activation of cystic fibrosis transmembrane conductance regulator ion channel. Finally, linaclotide helps to accelerate the intestinal motility and increase the intestinal fluid release. Additionally, a reduction of visceral pain after administration of linaclotide was observed in the pharmacology study on animal models. This may attribute to the increasing level of extracellular cGMP, causing a decrease in the activity of pain-sensing nerves.

Function

Since linaclotide helps to promote the bowel movements and increase the intestinal fluid, it can improve the constipation as a laxative. Linaclotide is developed to treat irritable bowel syndrome in patients with constipation or chronic constipation. After taking the drug, some adverse effects are commonly observed: more than 10% of people using linaclotide have diarrhea, and 1%-10% of people have symptoms including a decreased appetite, dehydration, low potassium, nausea, vomiting and bleeding in their colon, rectum and anus. Due to the high risk of dehydration in teenagers, the drug can't be used in patients less than 6 years old, and should be avoided to use in people between 6 and 18 years old.

Pharmacokinetics and metabolism

Linaclotide is not absorbed into the system when taken orally, thus the half-life can't be calculated. And it is expected to be minimally distributed to tissues, while no detectable levels of linaclotide were observed after 125mcg or 290mcg administration of linaclotide. Metabolism studies show that linaclotide is metabolized in the gastrointestinal tract to its active metabolite by loss of the terminal tyrosine moiety. And most of linaclotide and its active metabolite undergoes proteolysis in the intestinal lumen before it's excreted via feces.